HSV-1 is a common infection that can cause cold sores. In this study, the anti-HSV-1 virus activity of three series compounds A1-A9, B1-B12, C1-C22 was screened by MTT assay, qRT-PCR assay, Western blot assay and viruses\' plaque assays. The results of MTT assay disclosed that phloroglucinol derivatives C2 and C3 effectively inhibited the death of HSV-1 infected vero cells with the CC(50) values of C2 and C3 were 72.64 mumol/L and 32.62 mumol/L in HaCaT cells, 137.6 mumol/L and 48.55 mumol/L in Hela cells. The IC(50) values of C3 in vero cells and Hela cells were 19.26 mumol/L and 22.98 mumol/L, respectively. In the qRT-PCR experiments, it showed that C2 and C3 effectively reduced the synthesis of HSV-1 early viral gene VP16 and late viral gene gD. The Western blot results showed that both C2 and C3 inhibited the expression of HSV-1 gD protein in a concentration-dependent manner. Lastly, viruses\' plaque assay results showed that C2 and C3 inhibited the production of HSV-1 progeny virus in Hela cells and HaCaT cells in a concentration-dependent manner. Taken together, these results suggest that C2 and C3 are promising candidate that warrants further attention in the development of anti-HSV-1 drugs.